Protein Misfolding Disorders (PMDs) include several diverse diseases such as Alzheimer's disease (AD), Parkinson's disease, transmissible spongiform encephalopathies (TSEs, also known as prion disorders) and type 2 diabetes (T2D), among many others. The central event in these diseases is the accumulation of a misfolded form of a naturally expressed protein, which becomes toxic and induces tissue damage, organ dysfunction and disease. Despite the diversity of clinical symptoms associated to different PMDs, many similarities in their mechanism suggest that distinct pathologies may cross-talk at the molecular level to enhance each other. This proposal is structured around the hypothesis that misfolded proteins associated to one PMD might initiate or accelerate the pathogenic cascade of a second PMD-related disease through a cross-seeding mechanism. We plan to study this subject in a comprehensive way using various animal models and novel in vitro technologies developed in our lab. The studies will focus on 3 diseases of the PMD group: AD, T2D and TSEs. We have recently described the pathological interaction between misfolded prions (PrPSc) and amyloid- (A), the proteins implicated in TSEs and AD, respectively. Our results showed that both diseases were dramatically accelerated when the two misfolded proteins were present simultaneously in the brain. The information gathered from these studies encouraged us to pursue further this line of research, and expand it to assess the putative interaction between the two most prevalent PMDs: AD and T2D. The main goal of this project is to evaluate the molecular cross-talk between misfolded proteins as a pathogenic mechanism implicated in the initiation of these diseases. Experiments are designed to provide proof-of-concept data in animal models for a pathogenic interaction among these diseases and various in vitro studies to investigate if cross- seeding of protein misfolding may explain in part the disease interaction. We will also study whether the disease can be induced or accelerated through a medically relevant route of exposure (blood transfusion) to heterologous misfolded oligomeric aggregates. The findings generated in this project may provide a new paradigm to understand the etiology and molecular basis of highly prevalent and insidious diseases, such as AD, T2D and TSEs and may offer new avenues for developing strategies for disease prevention and intervention. PUBLIC HEALTH RELEVANCE: Some of the most debilitating and chronic human diseases involve the misfolding, aggregation and tissue accumulation of proteins. These protein misfolding diseases (PMDs) include highly prevalent diseases, such as type 2 diabetes and Alzheimer's disease. One of the most important unanswered questions regarding PMDs is to understand the factors and mechanisms involved in the initiation of the pathology. The overarching hypothesis of this project is that misfolded proteins associated to one PMD might initiate or accelerate the pathogenic cascade of a second PMD-related disease through a cross-seeding mechanism. This hypothesis will be comprehensible tested using various in vivo and in vitro studies in models of Alzheimer's disease, type 2 diabetes and prion diseases. The results obtained in this study may open a new view to understand the origin of some of the most noxious forms of PMDs.